Each mammalian tissue is distinct in biochemical properties, as is necessitated by different functions and evidenced by different susceptibilities to pathologies and toxicities. Compounds containing peroxide functions are known to be toxic to heart and to be involved in pathologies involving other tissues. Although peroxides are known to be generated in heart, very little is known about peroxide metabolism and its biochemical consequences in the heart. The purpose of this proposal is to determine the pathways of peroxide metabolism in the heart and the relationship of this metabolism to cardiac pathophysiology and toxicology. The research program will be divided into three overlapping phases. Initially, the quantitatively-important pathways of metabolism of H2O2 and organic peroxides will be determined in isolated adult rat cardiac myocytes. Characteristic alterations in cellular biochemistry will be sought to provide a means to quantitate H2O2 generation in heart cells or perfused heart. The results of these studies will be used in the second phase to determine the extent of peroxide formation in response to toxic compounds (eg, redox cycling agents) and in pathologic conditions (eg, in the presence of activated neutrophils). The third phase will involve direct examination of the effects of peroxides on specific biochemical systems which have been shown to be sensitive to peroxides in other tissues. The results of these studies will provide new information on cardiac metabolism, specifically in relation to the disposition of peroxides, and may therefore provide new insight into heart function and failure.